The discovery of resident adult cardiac stem cells has generated interest in exploiting the heart's endogenous regenerative potential for the development of cell-based therapies to reverse myocyte loss and improve ventricular function in patients with ischemic heart disease. Cardiosphere-derived cells (CDCs) isolated from myocardial biopsies are a recently identified source of adult stem cells that promote cardiac regeneration and enhance contractile function through both direct differentiation into cardiac myocytes and by stimulating endogenous myocyte proliferation. To build on these initial results, attention has been directed towards identifying strategies to amplify CDC-mediated cardiac repair. One novel approach is to capitalize on the highly proliferative phenotype of cardiac cells in the heart during early postnatal development, which may provide a source for the derivation of CDCs with superior regenerative potential. Accordingly, the objective of this proposal is to test the central hypothesis that CDCs derived from the young heart during early postnatal cardiac development are superior to CDCs from the aged adult heart in promoting cardiac repair. To test this hypothesis, the efficacy of young heart-derived CDCs (Y-CDCs) and aged heart-derived CDCs (A-CDCs) will be compared following intracoronary administration in a large animal model of chronic ischemic heart disease. Specifically, Aim 1 will examine the capacity of each cell population to elicit improvements in myocardial contractile function and perfusion in swine with hibernating myocardium resulting from a chronic coronary stenosis. In Aim 2, the ability of Y-CDCs and A-CDCs to increase myocyte nuclear density, stimulate myocyte proliferation, mobilize endogenous progenitor cells, and differentiate into cardiac myocytes and blood vessels will be evaluated. To initiate exploration of potential mechanisms underlying the hypothesized differences between these cell populations, Y-CDC and A-CDC telomerase activity and telomere length will be assessed in Aim 3. Identification of superior regenerative properties of young heart-derived CDCs would lead to future work examining the cellular and molecular mechanisms underlying this functional benefit, as well as translational investigation of allogeneic young donor-derived CDC administration to older adults with heart disease. Moreover, advancements in methods of cell re-programming (e.g., induced pluripotent stem cells) may eventually allow researchers to recapitulate the youthful CDC phenotype in cells from older adults, ultimately leading to the development of novel strategies to optimize cardiac repair and prevent the progression of left ventricular dysfunction to clinical heart failure in patients wth coronary artery disease.